The present invention relates to enteral administration of adenosine and related nucleosides for restoration of adenosine triphosphate (ATP) and other energy substrates in splanchnic tissue following trauma, ischemia, and other conditions which compromise organ bioenergetic substrates.
Vasoconstriction of the major vessels of the splanchnic bed is one of the pathophysiologic events arising from gram-negative bacterial sepsis and shock. This event may also occur during surgical procedures involving these organs. Splanchnic organs normally have a low ambient pO.sub.2, and would therefore be susceptible to ischemic injury during septic or other types of shock. This hypoperfused state leads to tissue ischemia and build-up of lactate due to reduced pyruvate entry into the Krebs cycle for oxidative phosphorylation. The energy substrate content of a given organ may therefore be compromised during ischemic episodes by: (1) reduced capacity for ATP regeneration; and/or (2) increased ATP utilization.
If severe enough, these imbalances which arise during ischemic episodes could foster extensive dephosphorylation of ATP and other nucleotides to yield purine nucleosides or nucleobases (i.e., purines). The purines could then be irreversibly degraded or released due to their membrane permeable nature. Given that de novo synthesis of purines requires energy nd a variety of substrates, restoration of ATP in ischemic splanchnic tissues is presumably retarded.
For some organs, particularly the gut, de novo synthetic pathways for purines normally are not operative given the availability of purines in foods. Unfortunately, anorexia which accompanies infection or postsurgical stress diminishes food intake. As a consequence, post-ischemic recovery of gut tissue ATP could be retarded due to the reduced purine intake coupled with a reduced capacity of the gut for de novo purine synthesis. This may promote a leakiness in the gut wall and increase the potential for bacterial or endotoxin translocation.
Furthermore, intestinal tissues, such as the gut, normally rapidly turn over as enterocytes are sloughed off into the lumen. This rapid turnover places a great demand for ATP on gut tissue. In septic or traumatized states, therefore, reduced tissue content of ATP could retard enterocyte formation.
These catabolic events would foster conditions which enable bacterial or endotoxin translocation across the damaged or weakened gut wall. In the immune-compromised septic or post-operative patients, this condition could precipitate multiple organ failure.
Allograft liver dysfunction during post-transplant recovery is life-threatening, requiring re-transplantation or prolonged intensive care. Although the etiology of this dysfunction is unknown, liver synthetic function is retarded by a limited ATP supply. Extensive degradation of ATP (over 85%) during liver storage, coupled with the washout of salvageable precursors prior to implantation may render the liver conditionally deficient in ATP precursors and retard post-transplant ATP recovery.
In organ transplant situations, reduced ATP often inhibits successful transplant. Recent evidence indicates that the primary injury to the donor liver is associated with disruption of the sinusoidal endothelium during hypothermic preservation. Subsequent reperfusion injury to hepatocytes results from localized ischemia arising from microcirculatory disturbances. Prior to these events, liver adenine nucleotide content is substantially reduced within the first 4 hours of storage ex vivo. Since nucleotide synthesis de novo is both energy and substrate dependent, restoration of total adenine nucleotide content through the de novo pathway could be retarded by the decreased availability of ATP following preservation.
The release of salvageable precursors from the allograft liver during reflow can produce a conditional deficiency of substrates to further impede ATP recovery. A reduction in ATP synthetic capacity coupled with poor oxygenation during reflow could exacerbate parenchymal and nonparenchymal cell damage.
Exogenous adenosine is an effective substrate capable of augmenting or supporting hepatocellular ATP concentrations in vivo or in vitro. Exogenous adenosine has also been utilized to maintain ATP concentrations in dog liver subjected to extend perfusion preservation A recent study reports a correlation of ATP recovery with hepatocellular viability. In a similar fashion, perfusion of mouse livers with the nucleobase adenine following the imposition of 20 minutes of ischemia restored ATP concentrations to pre-ischemic levels, whereas ATP recovery in livers perfused without adenine was only 63% of normal.
There remains a need for an improved method of increasing energy levels of splanchnic tissue. Especially in transplant situations, organs have depleted energy stores and cannot de novo produce required metabolic energy.
Accordingly, it is an object of the invention to provide an improved method for increasing ATP levels in patients suffering from a form of splanchnic disorder.
It is another object of the invention to provide a total enteral nutrition diet for achieving and maintaining normal metabolic levels of ATP in a patient.
Another object is to provide improved absorptive capacity and intestinal tolerance to enteral feeding.
Yet another object is to provide adenosine with the other components of a complete diet to improve absorptive capacity and intestinal tolerance to enteral feeding. Other objects, features, and advantages of the invention will be apparent from the following drawings, description of the preferred embodiments, and from the claims.